| Background:Observational studies have indicated that depression is associated with cardiovascular diseases.Nevertheless,causal associations and directions between depression and cardiovascular diseases remain controversial.Hence,we conducted a Mendelian randomization(MR)study to evaluate the genetically determined associations between depression and cardiovascular diseases.Methods:Summary statistics from genome-wide association studies of depression(246,363 cases and 561,190 controls),and coronary artery disease(CAD)(60,801 cases,including 43,676 with myocardial infarction,and 123,504 controls)were used.A fixedeffects inverse-variance weighted(IVW)meta-analysis was used to combine the MR estimates as standard analysis.We conducted multivariable MR to intervene on influence of the potential cardiovascular risk factors on causal estimates.The mediation effects of potential cardiovascular risk factors on depression-CAD and myocardial infarction risk were investigated by using mediation analysis.We also explored the bidirectional associations between depression and other vascular outcomes,including heart failure,atrial fibrillation,stroke,ischemic stroke and its subtypes,and intracerebral hemorrhage.The bidirectional causality of depression with systolic and diastolic blood pressure was evaluated in the UK Biobank and the International Consortium of Blood Pressure Genome Wide Association Studies(757,601 individuals).We further explored the relationship of genetic liability to mean arterial pressure and pulse pressure at age ≤55(163,147 individuals)and >55(245,749 individuals)years with depression using data from UK Biobank.Results:In the IVW analyses,genetic liability to depression was associated with higher CAD(OR,1.14;95% CI,1.06–1.24;P=1.0×10-3)and myocardial infarction(OR,1.21;95% CI,1.11–1.33;P=2.8×10-5)risks.After adjusting for smoking or type 2 diabetes mellitus,our MR results demonstrated that there was no causal effect of depression on CAD or myocardial infarction.The mediation analysis showed that,the mediated proportion of smoking was 30.5%(95% CI,12.5% to 48.5%)on CAD,and 24.9%(95% CI,11.5% to 38.3%)on myocardial infarction,respectively.Likewise,the mediated proportion of type 2 diabetes mellitus was 41.2%(95% CI,17.9% to 64.4%)on CAD,and 24.1%(95% CI,9.4% to 38.8%)on myocardial infarction,respectively.Furthermore,our MR analyses revealed that the genetic liability to depression was associated with higher risks of heart failure(OR,1.11;95% CI,1.04–1.19;P=2.8×10-3)and small vessel stroke(OR,1.36;95% CI,1.11–1.65;P=2.4×10-3),but not with atrial fibrillation,stroke,any other ischemic stroke and its subtypes,or intracerebral hemorrhage.Conversely,genetically instrumented cardiovascular diseases were not associated with depression.Genetically determined depression was not associated with a higher systolic or diastolic blood pressure(β,-0.22;95% CI,-0.48,0.05;P=0.11 and β,0.03;95% CI,-0.12,0.19;P=0.66,respectively).Genetic predisposition to higher systolic and diastolic blood pressure,in turn,showed no relationship with depression(OR,1.00;95% CI,0.99–1.02;P=0.60 and OR,1.01;95% CI,1.00–1.02;P=0.18,respectively).There was no evidence showing a causal effect of elevated mean arterial pressure or pulse pressure at age ≤55 or >55 years on deprpession risk.Conclusions:Genetically determined depression is associated with higher CAD and myocardial infarction risks,partly mediated by smoking and type 2 diabetes mellitus.In addition,genetic liability to depression increased the risks of heart failure and small vessel stroke,whereas the relationship from cardiovascular diseases to depression is unlikely to be causal.There was no evidence showing a bidirectional causal effect between depression and blood pressure.Similarly,neither genetically predicted mean arterial pressure nor pulse pressure at age ≤55 and >55 years were associated with depression. |
PDF Full Text Request